Novobiocin is an antibiotic useful in the treatment of staphylococcal infections and in urinary tract infections caused by certain strains of Proteus. It shows no cross resistance with penicillin and is active against penicillin-resistant strains of Staphylococcus aureus. Novobiocin is produced through fermentation by streptomycetes. The methods for production, recovery and purification of novobiocin are described in U.S. Pat. No. 3,049,534.
Dihydronovobiocin is an antibiotic prepared by hydrogenating novobiocin according to the procedures disclosed in U.S. Pat. No. 3,175,944.
As with any antibiotic it is always highly advantageous to prepare derivatives or analogs since these often lead to new antibiotics with increased potency, fewer and less severe side effects, and/or a different spectrum of antibiotic activity. In 1972 U.S. Pat. No. 3,652,536 disclosed an enzymatic process for cleaving novobiocin to produce novenamine. U.S. Pat. No. 3,890,297 disclosed a selective process for N-acylation of novenamine which produces novobiocin analogs which have antibacterial activity.
The following patents disclose modifications of novobiocin: U.S. Pat. Nos. 2,925,411; 2,938,899; 2,945,064; 3,049,550; and 3,445,455; British Pat. Nos. 856,816 and 997,179; and German Pat. Nos. 1,088,982 and 1,076,144.
However none of the above relate to modification of the isopentenyl side chain on the benzamido ring. To my knowledge only the combined process of U.S. Pat. Nos. 3,652,536 and 3,890,297 disclosed a useful method for producing such analogs until the present invention.
Allylic oxidation with selenium dioxide is known. For a recent review see N. Rabjohn in Organic Reactions, Vol. 24, pp. 261-415 (1976). A set of rules ordering the susceptibility of carbon atoms in an olefin to oxidation by selenium dioxide were first given by A. Guillemonat in Ann. Chim., 11, 143 (1939). However, these rules are known to have exceptions as discussed by E. N. Trachtenberg (Oxidation, Techniques and Applications in Organic Synthesis, R. L. Augustine, Ed., Marcel Dekker, New York, 1969, Chapter 3) and V. T. Bhalero and H. Rapoport in J.A.C.S., 93, 4835 (1971). These exceptions and lack of appropriate examples in the literature preclude a priori predictability of the site of attack in an olefin such as that in the novobiocin-type compounds (I). The products could have been as follows: ##STR1## Since benzylic oxidation with selenium dioxide is known and since the above-cited rules state that methylene (--CH.sub.2 --) is oxidized prior to methyl (--CH.sub.3) and since the methylene group in question is both benzylic and allylic it is surprising and unexpected that the reaction is completely regioselective. The only products observed were those resulting from attack at the trans methyl group.